Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states.
Embryonic stem cells (ESCs) are apparently homogeneous self-renewing cells, but we observed heterogeneous expression of Stella in ESCs, which is a marker of pluripotency and germ cells. Here we show that, whereas Stella-positive ESCs were like the inner cell mass (ICM), Stella-negative cells were like the epiblast cells. These states were interchangeable, which reflects the metastability and plasticity of ESCs. The established equilibrium was skewed reversibly in the absence of signals from feeder cells, which caused a marked shift toward an epiblast-like state, while trichostatin A, an inhibitor of histone deactelylase, restored Stella-positive population. The two populations also showed different histone modifications and striking functional differences, as judged by their potential for differentiation. The Stella-negative ESCs were more like the postimplantation epiblast-derived stem cells (EpiSCs), albeit the stella locus was repressed by DNA methylation in the latter, which signifies a robust epigenetic boundary between ESCs and EpiSCs.
Hayashi
Katsuhiko
K
Wellcome Trust Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN United Kingdom.
de Sousa Lopes
Susana M Chuva
SMC
Wellcome Trust Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN United Kingdom.
Tang
Fuchou
F
Wellcome Trust Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN United Kingdom.
Lao
Kaiqin
K
Molecular Cell Biology, Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404, USA.
Surani
M Azim
MA
Wellcome Trust Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN United Kingdom.
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D053624:Blastocyst Inner Cell Mass / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D019175:DNA Methylation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000166:cytology / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006706:Homeostasis; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D000943:Antigens, Differentiation; D002868:Chromosomal Proteins, Non-Histone; C462180:Dppa3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; C012589:trichostatin A